Encapsulation of mesenchymal stromal cells in engineered microgels for resolution of lung fibrosis

将间充质基质细胞封装在工程微凝胶中以解决肺纤维化

• 批准号: 9894836
• 负责人: Jae-Won Shin
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894836
• 关键词: Address; Alginates; Antibodies; Biochemical; Biocompatible Materials; Biomedical Engineering; Biophysics; Cell Therapy; Cells; Chronic; Cicatrix; Collagen; Cues; Data; Dendritic Cells; Dendritic cell activation; Deposition; Diagnosis; Disease; Disease model; Encapsulated; Engineering; Extracellular Matrix; Fibrosis; Gel; Genetic; Glycocalyx; Hydrogels; Immune; Impairment; Inflammatory; Injury; Interstitial Collagenase; Ligands; Lung; Microencapsulations; Microfluidics; Modeling; Mus; Organ; Pathogenesis; Pathway interactions; Phenotype; Production; Property; Pulmonary Fibrosis; RGD (sequence); Research Personnel; Resolution; Respiratory physiology; Role; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Technology; Testing; Therapeutic; Thinness; Time; Tissues; Transplantation; Tumor Necrosis Factor Activation; Tumor Necrosis Factor Receptor; Work; base; biophysical techniques; collagenase; curative treatments; cytokine; design; effective therapy; idiopathic pulmonary fibrosis; improved; in vivo; knock-down; member; mesenchymal stromal cell; multidisciplinary; novel; prevent; programs; public health relevance; residence; response; screening; stem cells

PROJECT SUMMARY The ability of mesenchymal stromal cells (MSCs) to adapt to their tissue niche and remodel extracellular matrix (ECM) could be therapeutically beneficial in treating fibrotic diseases. However, leveraging this property has been challenging because MSCs are rapidly cleared from tissue once delivered. Thus, specific pathways to induce MSCs to remodel the ECM and the utility of these remain unclear. We described herein a highly efficient approach to encapsulate single cells in engineered microgels with predefined biochemical and biophysical cues. We have fine-tuned this approach to show that clearance of MSCs is significantly delayed when they are delivered in thin microgels intratracheally to lungs. Importantly, our preliminary data show that this treatment decreases collagen accumulation in a murine lung fibrosis model. We show in these supporting studies amplified ability of MSCs to degrade collagen-I when the cells are encapsulated in engineered hydrogels with tunable stiffness. In this my first RO1 proposal, I will build upon these results to test the hypothesis that programming of MSCs using specifically engineered microgels activates the potential of MSCs to promote resolution of fibrosis and thus restore lung function. In Aim 1, we will determine the role of microencapsulation in controlling retention of MSCs in lungs and facilitating resolution of lung fibrosis. In Aim 2, we will determine the potentially important role of the inflammatory cytokine tumor necrosis factor-α (TNFα) in modifying the phenotype of microencapsulated MSCs to produce high amounts collagenases with enhanced potential to resolve lung fibrosis. We predict that selectively activating TNF receptor 2 in MSCs encapsulated in soft microgels can resolve lung fibrosis. The project is highly multidisciplinary in that it will employ a combination of expertise in biomaterials, lung fibrosis, biophysical, genetic, and mouse in vivo approaches to address the specific aims. The results will help to define how MSCs can facilitate resolution of fibrosis through prolonging their in vivo residence time in lungs, and modifying their phenotype through encapsulation in engineered and tunable microgels to optimize their production of collagenases. We thus hope to develop novel MSC based approaches to remodel aberrant extracellular matrix and to treat lung fibrosis. !

项目摘要 间充质基质细胞（MSC）适应其组织生态位和重塑细胞外基质的能力 （ECM）可能对治疗纤维化疾病具有热有益。但是，利用此属性具有 之所以挑战，是因为一旦输送的组织就可以从组织中迅速清除MSC。那，到达的特定途径 诱导MSC重塑ECM，并且这些效用尚不清楚。我们在这里描述了一个高度 用预定义的生化和 生物物理提示。我们对这种方法进行了微调，以表明MSC的清除率显着延迟 当它们在气管内稀薄的微焦层中递送到肺部时。重要的是，我们的初步数据表明 这种处理可减少鼠肺纤维化模型中的胶原蛋白积累。我们在这些支持中显示 研究将细胞封装在工程中时，MSC降解胶原蛋白I的能力放大了 具有可调刚度的水凝胶。在这是我的第一个RO1建议中，我将基于这些结果来测试 假设使用特定设计的微凝胶编程MSC会激活MSC的潜力 促进纤维化的分辨率，从而恢复肺功能。在AIM 1中，我们将确定 控制MSC在肺部保留和支持肺纤维化的分辨率方面的微囊化。在AIM 2中， 我们将确定炎性细胞因子肿瘤坏死因子-α（TNFα）在中的潜在重要作用 修改微囊化MSC的表型，以产生高量的胶原酶，并增强 解决肺纤维化的潜力。我们预测，在封装在MSC中的MSC中有选择地激活TNF受体2 软微凝胶可以解决肺纤维化。该项目是高度多学科的，因为它将采用 生物材料，肺纤维化，生物物理，遗传和小鼠体内的专业知识的结合 解决具体目标。结果将有助于定义MSC如何通过 延长其在肺部的体内停留时间，并通过封装来修改其表型 设计和可调的微凝胶，以优化其胶原酶的产生。因此，我们希望发展小说 基于MSC的重塑异常细胞外基质和治疗肺纤维化的方法。 呢